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  1. 1. IOSR Journal of Applied Chemistry (IOSR-JAC)e-ISSN: 2278-5736. Volume 3, Issue 4 (Jan. – Feb. 2013), PP 74-80www.iosrjournals.org Ammonium chloride catalyzed microwave-assisted Claisen- Schmidt reaction between ketones and aldehydes under solvent- free conditions Rammohan PalDepartment of Chemistry, Acharya Jagadish Chandra Bose College, 1/1B, A. J. C. Bose Road, Kolkata 700020, West Bengal, IndiaAbstract: It has been found that ammonium chloride, which is a very inexpensive and readily availablereagent, can efficiently catalyzed Claisen-Schmidt reaction between ketones and aldehydes. α,α-Bis(arylmethylene)cycloalkanones, α,α-bis(cinnamylidene)cycloalkanones, α-cinnamylideneacetophenones andchalcones were afforded by reaction of ketones and aldehydes under microwave assisted solvent-free conditionsin presence of ammonium chloride in good to excellent yields.Keywords: Claisen-Schmidt reaction, Ammonium chloride, Microwave irradiation, Solvent-free conditions,Eco-friendly I. Introduction It is well known that α,α-bis(arylmethylene)cycloalkanones, chalcones and related compounds are usedas starting materials for synthesis of a variety of other interesting compounds 1-3 and exihibit a wide range ofbiological activities such as antibacterial and antitumor properties4. The principal synthetic routes avenues tothese compounds comprise the base, protic and Lewis acid catalyzed reaction of ketomethyl or ketomethylenecompounds with aldehydes. In view of that, several synthetic methods for the preparation of such compoundshave been reported by using catalysts such as: solid NaOH5, BF3.OEt26, InCl37, InCl3/TMSCl8, TiCl3(SO3CF3) 9,TMSCl/NaI10, Yb(OTf)311, Cu(OTf)212, RuCl313, FeCl314, SmI315, silica surfuric acid16, KF/inorganic solidsupport17, Co(II)-bipyridyl18, Molecular Iodine19 and SOCl220. Microwave irradiation methods were alsoreported using KF-Al2O321, NaOH22, acidic alumina23, Na2CO3-TBAB (PTC condition)24 and bis(p-methoxyphenyl)telluroxide25 as catalysts. Most of these methods suffer from various disadvantages such as longreaction periods [e.g. 10 hrs using Cp2ZrH2/NiCl226], use of expensive Lewis acids [e.g. amberlyst-1527 andB2O3/ZrO2 or SO42-/ZrO228], use of hazardous catalyst [e.g. iodine19]. Moreover, none of these methods isenvironmentally friendly, since always an excess of solvent and often toxic or hazardous chemicals areemployed. Due to these problems, development of an efficient and versatile method for the preparation of α,α-bis(arylmethylene)cycloalkanones, chalcone and related compounds are an important aspect and which is anactive going on research area and there is a scope for the further improvement towards mild reaction conditionsand improved yields. Ammonium chloride has been reported as catalyst for synthesis of various organic compounds. It isefficiently promoted Ugi four-component reactions30, four-component synthesis of pyrrolo[3,4-b]pyridones31and one-pot synthesis of imidazole[1,2-a]pyridines32. Moreover ammonium chloride was effectively used ascatalyst for aliphatic Claisen rearrangement33, reduction of azo compounds to their corresponding hydrazine34,reduction of nitrophenols in aqueous media35 and under ultrasound36, reductive cleavage of azo compounds37,synthesis of diindolylmethanes38, synthesis of spirochromenes and spiroacridines compounds39 and Biginellisynthesis of 3,4-dihydropyrimidinones under solvent-free conditions40. Recently, Teimouri et al.41 weresynthesized α,α-bis(substituted benzylidene)cycloalkanones using ammonium chloride in ethanol underrefluxing conditions within 3.5 to 5 hrs. There is an increasing interest in the use of environmentally feasibleregents particularly in solvent-free conditions and also reduction of reaction times. Prevention of organicsolvents during reactions in organic synthesis leads to a clean, efficient, and economical technology; not onlywith the reduction of cost, but also increased amounts of reactants can be achieved in the same equipmentwithout huge modification. A survey of the literature revealed that the reaction between cycloalkanones andaromatic aldehydes using ammonium chloride under microwave irradiation has not been studied so far. In continuation of this research, I herein report the rapid synthesis of α,α-bis(arylmethylene)cycloalkanones, α,α-bis(cinnamylidene)cycloalkanones, α-cinnamylideneacetophenones andchalcones using ammonium chloride as a environmentally friendly catalyst using microwave irradiation undersolvent-free conditions (Scheme 1 & 2). www.iosrjournals.org 74 | Page
  2. 2. Ammonium chloride catalyzed microwave-assisted Claisen-Schmidt reaction between ketones and II. Results And Discussion In this methodology, several aromatic aldehydes were rapidly reacted with cyclohexanone andcyclopentanone when subjected to microwave irradiation in presence of ammonium chloride under solvent-freeconditions. The condensation proceeded smoothly to form ,-bis(arylmethylene)cyclohexanones (3a-f) and,-bis(arylmethylene)cyclopentanones (3g-k), respectively, in very good yield (73-95%) (Scheme 1, Table 2).Furfuraldehyde and cinnamaldehyde also reacted with the said cyclic ketones in the similar way. O CHO O NH4Cl (0.5 eq.) + ( )n M.W.; 3 min. ( )n R R R n = 1, 0 1 2 3a-f : n= 1 3g-k : n= 0 Scheme 1To achive the best results for this reaction (Scheme 1) we have studied the synthesis of ,-bis(phenylmethylene)cyclohexanone (3a, entry a, Table 2) as a model substrate with using various amount ofcatalyst (0.25, 0.50 and 0.75 mmol) in different reaction times. For each reaction condition, conversion ofbenzaldehyde (2 mmol) and cyclohexanone (1 mmol) to 3a was realized by TLC using silica-gel G of SRL Pvt.Ltd. Table 1. Optimization of catalyst content and reaction time. Catalyst (eq.) Reaction time (min) Conversion (%) 0.25 1 40 0.25 2 55 0.25 3 63 0.5 1 71 0.5 2 90 0.5 3 99 0.75 1 75 0.75 2 94 0.75 3 98As shown in Table 1, the most satisfactory results were obtained with a 2:1:0.5 ratios of benzaldehyde,cyclohexanone and ammonium chloride for 3 min. The experimental procedure is very simple and the conversion occurs in short irradiation time of ca. 3min. After irradiation the mixture was cooled, poured in ethanol, and filtered. After evaporation of the solventscorresponding condensation products were recovered in crystalline forms. The reactions were clean and freefrom side products such as self condensation of ketones. The presence of electron donating or electronwithdrawing group in the aromatic aldehyde did not show any significant effect on the rate of conversion underthe present experimental condition. When this reaction was carried out under thermal condition in refluxingacetonitrile a longer time (6 hrs.) was required and the yields of the products were also low (40-50%). After getting success in condensation of cycloalkanones with aromatic aldehydes and relatedcompounds, I turned my attention to apply this methodology for synthesis of chalcones and related compoundswhich are also well-known for their biological activities as well as for their easy transformation to otherbiologically active compounds. Thus, when acetophenone and benzaldehyde or cinnamaldehyde were used, thedesired chalcones and related compounds were obtained in 70-88% yield (Scheme 2, Table 3). www.iosrjournals.org 75 | Page
  3. 3. Ammonium chloride catalyzed microwave-assisted Claisen-Schmidt reaction between ketones and O O [ CHO NH Cl (0.5 eq.) [ ] CH3 ]n 4 n + M.W.; 3 min. R R 1 1 R R R = H, CH3 n = 1, 0 n = 1, 0 4 5 6 Scheme 2The catalytic role of ammonium chloride in the above process was clearly evident from the observation that inits absence no reaction took place. Neutral alumina used acted as solid support only, and this view corroboratesthe findings of Esmaeili et al.23 H O Ph O OH O O O H H H NH3 H NH4 H Ph NH4 Ph 3a -H 2O ) PhCHO H NH3 A B C Scheme 3Scheme 3 briefly shows the catalytic behavior of ammonium chloride throughout the predicted mechanisticpathway for the preparation of 3a. Ammonium chloride could activate the carbonyls of cyclohexanone forformation of enol A as well as the nucleophilic attack of A to benzaldehyde which formed an intermediate B.The intermediate B again activated for dehydration by formation of hydrogen bonding of its hydroxyl groupwith NH4Cl which formed C. Repetition of these processes formed 3a. My findings (Table 2 & 3) reflect the wide applicability and usefulness of the method. Some previouslyreported data (Table 4) on reaction conditions and yield of product for preparation of ,-bis(phenylmethylene)cyclohexanone (entry a, Table 2) were compared with this results. As one can see theresults show a very good comparability with previously reported data particularly Teimouri et al.41 in order toyields and reaction times. Table 4. Comparison own result with reported previously data for synthesis of ,-bis(phenylmethylene)- cyclohexanone (3a). Catalyst Reaction condition Time Catalyst Yield Ref. content (%) Indium trichloride Solvent-free, 110ºC 6 hr 0.1 mmol 95 7 Copper triflet Solvent-free, 80ºC 6 hr 0.05 mmol 94 12 Iodine Solvent-free, 60-65ºC 10 min 0.1 mmol 93 19 Ytterbium triflet Solvent-free, 90ºC 6 hr 0.025 mmol 92 11 Ruthenium trichloride Solvent-free, 120ºC 6 hr 0.1 mmol 95 13 Silica sulfuric acid Solvent-free, 80ºC 2.5 hr 4 mmol 91 16 SO42-/ZrO2 or B2O3/ZrO2 Solvent-free, MW 18 min unspecified 96 28 Amberlyst-15 Solvent-free, MW 3 min 100 mg 80 27 KF-Al2O3 Solvent-free, MW 4 min 37 % (w/w) 90 21 Acidic alumina Solvent-free, MW 3.5 min 4 gm 97 23 Ammonium chloride Ethanol, Reflux 5 hr 0.5 mmol 91 41 Ammonium chloride Solvent-free, MW 3 min 0.5 mmol 95 Present work www.iosrjournals.org 76 | Page
  4. 4. Ammonium chloride catalyzed microwave-assisted Claisen-Schmidt reaction between ketones and Table 2. Results of Microwave assisted Claisen-Schmidt reaction between cycloalkanones and aldehydes catalyzed by ammonium chloride. Isolated Mp/ ºCEntry Ketone Aldehyde Product Yield Found Reported (1) (2) (3)a (%)b O CHO O a 95 114 115-11621 O CHO O b 81 203-205 20523 CH3O OCH3 OCH3 O CHO O c 79 164-166 16816 CH3 CH3 CH3 O CHO O d 90 137 13827 Cl Cl Cl O O O O 143-14523 O CHO e 78 140-142 O CHO O O O f 79 180-182 18427 O O O O O CHO O g 82 190 190-19116 O CHO O h 73 213-215 212-21516 CH3O OCH3 OMe O CHO O i 87 227-239 22516 Cl Cl Cl O O O O 204-20519 O CHO j 80 204 O CHO O O O k 74 259-261 26227 O O O O O CH=CHCHO O l 81 178 178-18021 O CH=CHCHO O m 84 219-221 222-22421a All products were identified by their melting points and spectral data; bIsolated yields. www.iosrjournals.org 77 | Page
  5. 5. Ammonium chloride catalyzed microwave-assisted Claisen-Schmidt reaction between ketones and Table 3. Results of Microwave assisted Claisen-Schmidt reaction between acetophenones and aldehydes catalyzed by ammonium chloride. Yield Mp/ ºC Entry Ketone Aldehyde Product (%)b (4) (5) (6)a Found Reported O CH=CHCHO O a CH3 Ph 70 84-85 8627 O CH=CHCHO O b CH3 Ph 75 122 120-12127 NO2 NO2 O CH=CHCHO O CH3 c CH3O Ph 78 74-75 76-7827 CH3O O CH=CHCHO O CH3 d Ph 82 133-135 Cl 13627 Cl O CH=CHCHO O CH3 e CH3 Ph 85 77 78-8027 CH3 O CHO O f CH3 96 56 56-5720 CHO O g O 87 68-70 69-715 CH3 OMe OCH3 O CHO O h CH3 78 110-112 111-1135 Cl Cl O CHO O CH3 i CH3 O O O CH3 O 90 110 11227a All products were identified by their melting points and spectral data. bIsolated yields after crystallization inethanol. www.iosrjournals.org 78 | Page
  6. 6. Ammonium chloride catalyzed microwave-assisted Claisen-Schmidt reaction between ketones and III. Experimental1.1. Chemicals and Apparatus All the chemicals used in the present study are of analytical grade and were obtained from localsuppliers. Melting points were determined on a Kofler block and uncorrected. IR spectra were recorded onPerkin Elmer FT-IR Spectrophotometer (Spectrum RX 1) and Jasco FT-IR-4200 Spectrophotometer as KBrpellets. 1H and 13C NMR spectra were obtained in CDCl3 on a Bruker AV-300 (300 MHz) spectrometers usingTMS as an internal standard. Analytical samples were dried in vacuo at room temperature. Microanalytical datawere recorded on two Perkin-Elmer 2400 Series II C, H, N analyzers. Column chromatograpy were performedon silica gel (100-200 mesh) using petroleum ether (60-80ºC)-ethyl acetate mixture as eluents. TLC was carriedout on silica gel G.1.2. General procedure Ketone (1 mmol), aldehyde (2 mmol for 3a-m or 1 mmol for 6a-i) neutral alumina (2 g), andammonium chloride (0.03 g, 0.5 mmol) were mixed thoroughly with the help of mortar pastle and the mixturewas taken in a Pyrex beaker (10 mL). The solid mixture was irradiated under a microwave (LG, MH-4048GW,480 W, 3 min). After completion of reaction indicated by TLC, the reaction mixture was cooled to roomtemperature, poured in ethanol, and filtered. After evaporation of the solvents corresponding condensationproducts were recovered in crystalline forms. The products were characterized from their IR, 1H NMR and 13CNMR spectroscopy. The characteristics data of some representative compound are given below.1.3. Analytical and Spectral data of some selected compounds 2,6-Bis(piperanyl)cyclohexanone (3f): Yellow crystalline solid. m.p. 180-182ºC. FT-IR (KBr): 3050,2930, 1682 (C=O), 1595 (C=C), 1210, 756 cm-1; 1H NMR (CDCl3, 300 MHz): δ 7.70 (br. s., 2H), 7.00 (br. d.,2H, J = 7.5 Hz), 6.98 (s, 2H, =CH), 6.85 (d, 2H, J = 8.4 Hz), 6.01 (s, 4H, -OCH2O-), 2.87-2.92 (dt, 4H), 1.76-1.84 (quintet, 2H); 13C NMR (CDCl3, 75 MHz); δ 190.1 (C=O), 148.1, 147.7, 136.6, 134.6, 130.2, 125.8, 110.1,108.4, 101.3, 28.5, 22.9. Anal. Calcd for C22H18O5 (362): C, 72.92; H, 5.01. Found: C, 72.68; H, 5.12%. 2,5-Bis(cinnamylidene)cyclopentanone (3m): Yellow crystalline solid. m.p. 219-221ºC. FT-IR (KBr):3019, 2909, 1674 (C=O), 1615 (C=C), 1203, 755 cm-1; 1H NMR (CDCl3, 300 MHz): δ 7.03-7.52 (m, 12H),6.95-7.02 (m, 4H), 2.92 (s, 4H). α-Cinnamylidene-4-methylacetophenone (6e): Yellow crystalline solid. m.p. 77ºC. FT-IR (KBr)): 3041,2953, 1652 (C=O), 1600 (C=C), 1199, 743 cm-1; 1H NMR (CDCl3, 300 MHz): δ 7.89 (d, 2H, J = 8.1 Hz), 7.60(ddd, 1H, J = 15.3, 7.2 & 3.0 Hz), 7.50 (dd, 2H, J = 6.9 & 1.3 Hz), 7.27-7.40 (m, 5H), 7.10 (d, 1H, J = 17.2 Hz),6.97-7.05 (m, 2H), 2.43 (s, 3H, CH3). 4-Methyl-α-piperanylacetophenone (6i): Yellow crystalline solid. m.p. 110ºC. FT-IR (KBr)): 3060,2933, 1675 (C=O), 1590 (C=C), 1220, 770 cm-1; 1H NMR (CDCl3, 300 MHz): δ 7.92 (d, 2H, J = 8.1 Hz), 7.73(d, 1H, J = 15.6 Hz), 7.37 (d, 1H, J = 15.6 Hz), 7.29 (d, 2H, J = 8.1 Hz), 7.17 (d, 1H, J = 1.5 Hz), 7.11 (dd, 1H,J = 8.0 Hz & 1.5 Hz), 6.83 (d, 1H, J = 7.8 Hz), 6.00 (s, 2H, -OCH2O-), 2.43 (s, 3H, CH3); 13C NMR (CDCl3, 75MHz): δ 189.9 (C=O), 149.8, 148.3, 144.2, 143.4, 135.8, 129.7, 129.2, 128.5, 125.1, 120.2, 108.6, 106.6, 101.6,21.65 (CH3). Anal. Calcd for C17H14O3 (266): C, 76.68; H, 5.30. Found: C, 80.55; H, 5.21%. IV. Conclusions In Conclusion, I have developed an economically and environmentally friendly catalyser for simple andefficient synthesis of α,α-bis(arylmethylene)cycloalkanones, α,α-bis(cinnamylidene)cycloalkanones, α-cinnamylideneacetophenones and chalcones in relatively short reaction times using microwave irradiation undersolvent-free reaction conditions. This involves the use of NH4Cl as a very inexpensive and easily availablecatalyst under neutral and solvent free conditions. Present methodology offers very attractive features such asreduced reaction times, higher yields and economic viability of the catalyst, when compared with othercatalysts, which will have wide scope in organic synthesis. Acknowledgements Financial support from the University Grants Commission, New Delhi, Government of India (UGCMRP Grant no. PSW-130/11-12-ERO) is gratefully acknowledged. Author also thanks the authorities of A. J. C.Bose College for providing infrastructural facilities. References[1] Li J-T, Lin Z-P & Liu C-T, Indian J Chem, 47B, (2008), 283.[2] Rashinkar G S, Pore S B, Mote K B & Salunkhe R S, Indian J Chem, 48B, (2009), 606.[3] Das B C, Marippan G, Saha S, Bhowmik D & Chiranjib, J Chem Pharm Res, 2, (2010), 113. www.iosrjournals.org 79 | Page
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